Pharmacological depletion of RNA splicing factor RBM39 by indisulam synergizes with PARP inhibitors in high-grade serous ovarian carcinoma

Yuewei Xu; Sarah Spear; Yurui Ma; Marc P. Lorentzen; Michael Gruet; Flora McKinney; Yitao Xu; Chiharu Wickremesinghe; Madelen R. Shepherd; Iain McNeish; Hector C. Keun; Anke Nijhuis

Cell Reports (Oct 2023)

Pharmacological depletion of RNA splicing factor RBM39 by indisulam synergizes with PARP inhibitors in high-grade serous ovarian carcinoma

Yuewei Xu,
Sarah Spear,
Yurui Ma,
Marc P. Lorentzen,
Michael Gruet,
Flora McKinney,
Yitao Xu,
Chiharu Wickremesinghe,
Madelen R. Shepherd,
Iain McNeish,
Hector C. Keun,
Anke Nijhuis

Affiliations

Yuewei Xu: Department of Surgery & Cancer, Imperial College London, London, UK
Sarah Spear: Department of Surgery & Cancer, Imperial College London, London, UK; Ovarian Cancer Action Research Centre, Department of Surgery & Cancer, Imperial College London, London, UK
Yurui Ma: Department of Surgery & Cancer, Imperial College London, London, UK
Marc P. Lorentzen: Department of Surgery & Cancer, Imperial College London, London, UK; Ovarian Cancer Action Research Centre, Department of Surgery & Cancer, Imperial College London, London, UK
Michael Gruet: Department of Surgery & Cancer, Imperial College London, London, UK
Flora McKinney: Department of Surgery & Cancer, Imperial College London, London, UK
Yitao Xu: Department of Surgery & Cancer, Imperial College London, London, UK
Chiharu Wickremesinghe: Department of Surgery & Cancer, Imperial College London, London, UK; Ovarian Cancer Action Research Centre, Department of Surgery & Cancer, Imperial College London, London, UK
Madelen R. Shepherd: Department of Surgery & Cancer, Imperial College London, London, UK
Iain McNeish: Department of Surgery & Cancer, Imperial College London, London, UK; Ovarian Cancer Action Research Centre, Department of Surgery & Cancer, Imperial College London, London, UK
Hector C. Keun: Department of Surgery & Cancer, Imperial College London, London, UK; Ovarian Cancer Action Research Centre, Department of Surgery & Cancer, Imperial College London, London, UK; Corresponding author
Anke Nijhuis: Department of Surgery & Cancer, Imperial College London, London, UK; Ovarian Cancer Action Research Centre, Department of Surgery & Cancer, Imperial College London, London, UK; Corresponding author

Journal volume & issue: Vol. 42, no. 10
p. 113307

Abstract

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Summary: Ovarian high-grade serous carcinoma (HGSC) is the most common subtype of ovarian cancer with limited therapeutic options and a poor prognosis. In recent years, poly-ADP ribose polymerase (PARP) inhibitors have demonstrated significant clinical benefits, especially in patients with BRCA1/2 mutations. However, acquired drug resistance and relapse is a major challenge. Indisulam (E7070) has been identified as a molecular glue that brings together splicing factor RBM39 and DCAF15 E3 ubiquitin ligase resulting in polyubiquitination, degradation, and subsequent RNA splicing defects. In this work, we demonstrate that the loss of RBM39 induces splicing defects in key DNA damage repair genes in ovarian cancer, leading to increased sensitivity to cisplatin and various PARP inhibitors. The addition of indisulam also improved olaparib response in mice bearing PARP inhibitor-resistant tumors. These findings demonstrate that combining RBM39 degraders and PARP inhibitors is a promising therapeutic approach to improve PARP inhibitor response in ovarian HGSC.

CP: Cancer

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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